The investigators have applied a stable expression cDNA cloning technology to search for novel human oncogenes, which might be undetectable by conventional techniques. By use of this strategy, they have isolated a novel ras- related oncogene, which contains a single base substitution at a position analogous to codon 61, known to activate ras oncogenes. In many human malignancies, oncogenes remain to be identified. The potent transforming properties of the TC21 oncogene, their preliminary findings that additional TC21 oncogenes can be identified in human tumor cells, the ubiquitous expression of ras-related genes in many tissues, and the lack of predictability of the prevalence of previously identified ras oncogenes despite their high frequency in a number of tumor types, all serve to justify systematic efforts to implicate ras related oncogenes in human tumors and determine their prevalence with respect to prototype ras. Approaches will involve immunologic screening combined with SCCP analysis to search for activating lesions affecting these genes in human tumor cell lines and primary tumors. They will develop models in tissue culture and in vivo including transgene targeting to confirm that the genetic alterations observed contribute importantly to the neoplastic process. Finally, they seek to compare their biochemical signaling properties with those of prototype ras, and correlate any differences observed with transforming potency in model cell systems. These studies should aid in elucidating differences in signaling functions which may account for differences in the prevalence of these oncogenes in various tumor types.